Osteoporosis is a disabling condition characterized by loss of bone mass. There is strong evidence that bone density is highly heritable, although the genes involved are largely unknown. Recent studies have implicated the vitamin D receptor, although the importance of this gene in modulating bone metabolism is controversial. The overall goal of the proposed study is to identify and characterize the genetic determinants of low bone density. The study population will consist of 750 individuals, aged 20 yrs and older, who are prior participants of the San Antonio Family Heart Study (SAFHS). During the baseline examination of the SAFHS (1992-1996), extensive interviews were obtained from all individuals on a wide range of medical and lifestyle variables, including dietary habits and physical activity levels. Blood samples were also drawn and DNA was collected for genetic analysis. In the proposed study, these individuals will be re-examined, and bone density will be measured at three sites by dual-photon absorptiometry (DEXA). Additional biochemical markers of bone density-related phenotypes will also be obtained. Eight candidate genes for osteoporosis will be genotyped, including the vitamin D receptor locus. Under separate funding (as part of the renewal for the SAFHS), funding has already been proposed to genotype a panel of 391 microsatellite markers spanning the genome at approximately 10cM intervals. Statistical genetic analyses will be performed to determine the effect of the vitamin D receptor locus, and of the other candidate genes, on bone density and related traits. Evidence for major genes will be detected through segregation analysis. These genes will then be mapped to chromosomal regions using the panel of microsatellite markers. Finally, they will test whether the genetic effects on bone density are modified by environmental factors. For example, they will determine if calcium intake or physical activity is more strongly correlated with bone density in individuals with the high risk vitamin D receptor genotype than in individuals with the lower risk genotypes at this locus.